Multiple chromosomal and genetic abnormalities have been described in MGUS, SMM and MM, and are thought to be important for disease pathogenesis and disease progression. The two most common abnormalities are translocations involving the immunoglobulin heavy chain locus (IgH) and aneuploidy. We and others have recently found that certain cytogenetic abnormalities have specific association patterns allowing for the cytogenetic subclassification of the disease. This has allowed the paradigm change that states that MM is not one disease, but rather several, that may be best discerned according to the underlying cytogenetic aberrations. We question; [unreadable] Can we establish that IgH translocations are seminal events in the pathogenesis of some patients with MGUS and MM? [unreadable] Can we better describe the transcriptional upregulation consequences of the IgH translocations? [unreadable] Can the study of MGUS and MM cytogenetics further elucidate pathogenic pathways for the disease? [unreadable] Do patients that develop MGUS and MM have an underlying susceptibility to acquire IgH translocations? SPECIFIC AIM 1: We wish to validate the biologic importance of IgH translocations for the pathogenesis of PC neoplasms. To do this we propose to determine the actual proportion of PCs in MGUS that share signature IgH translocation using simultaneous clg-FISH and ASO mRNA FISH. We also wish to establish the persistence, and potential expansion of PCs with IgH translocations in serial samples of MGUS/MM and subclones of the human MM cell lines SPECIFIC AIM 2: We will determine whether there are genetic subcategories of MGUS as in MM, Le. hyperdiploid and non-hyperdiploid MGUS. To do so we proposed detailed description of the disease using interphase FISH and by performing supervised clustering analysis of the gene expression profiles of MGUS and MM according to the cytogenetic category; primary IgH translocations, secondary IgH translocations and no IgH translocations. SPECIFIC AIM 3: Lastly we believe there is a possibility of inherent predisposition to IgH translocations in patients with MGUS and MM with IgH translocations. To find whether such a propensity exist we propose to use surrogate markers of DNA repair problems in patients at risk for MGUS and MM. We will then study the peripheral blood of patients with various PC proliferative disorders to detect and quantify 19HIbcl-2 PCR products.